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Respiratory System

Asthma

Chronic inflammatory disease of the airways associated with airway hyperresponsiveness leading to recurrent episodes of wheezing, breathlessness, chest tightness and/or coughing that can vary over time and in intensity.

Chronic inflammatory disease of the airways associated with airway hyperresponsiveness leading to recurrent episodes of wheezing, breathlessness, chest tightness and/or coughing that can vary over time and in intensity.

  • M/C chronic disease of childhood

History:

The modern concept of asthma as an immunologic disorder has its foundations in clinical observations spanning two centuries. This included early descriptions of “asthmatic sputum” associated with specific cell types, Charcot–Leyden crystals, and Curshmann spirals, inflammation of smaller airways, and paroxysms induced by environmental exposures. In the early 1920s, specific mechanisms for allergic diseases including asthma, allergic rhinitis, and atopic dermatitis were identified to be mediated by serum substances known as reagins. This was first exemplified by the passive transfer of fish hypersensitivity from one individual to another. Carl Prausnitz observed that his colleague Hans Küstner was exceptionally sensitive to cooked fish. To determine if this sensitivity was due to serum factors, he self-administered an intradermal injection of serum from his colleague and subsequently developed a new hypersensitivity to fish at the site of injection. Subsequently, it was shown that this transfer of skin sensitization, the Prausnitz–Küstner reaction, was mediated by a newly identified antibody class, IgE, which mediated hypersensitivity reactions to a wide range of allergens in multiple tissues including the lung. Today, approximately 60 % of asthma is linked to IgE-mediated reactions, and IgE remains one of the best predictors for the development of allergic asthma in humans. Further unpacking of these initial key discoveries has informed our modern understanding of asthma immunology and the importance of IgE in this process.

Timeline of asthma discoveries
Timeline of asthma discoveries | Harper, R. W., & Zeki, A. A. (2015). Immunobiology of the critical asthma syndrome. Clinical Reviews in Allergy & Immunology, 48(1), 54–65. https://doi.org/10.1007/s12016-013-8407-6

Epidemiology

Prevalence of symptoms of asthma in the past 12 months among persons aged 18 to 45 years in 70 countries
Prevalence of symptoms of asthma in the past 12 months among persons aged 18 to 45 years in 70 countries, Worlds Health Survey 2002–2003. | To T, et al. BMC Public Health 2012.

Etiology

The interplay of the environment and host susceptibility factors in the pathogenesis of asthma exacerbation
The interplay of the environment and host susceptibility factors in the pathogenesis of asthma exacerbations. | Bateman et al. JACI 2015;135:1457–1464.

Asthma subphenotypes:

Selected asthma subphenotypes
Selected asthma subphenotypes | Holgate, S. T., Wenzel, S., Postma, D. S., Weiss, S. T., Renz, H., & Sly, P. D. (2015). Asthma. Nature Reviews Disease Primers, 1(1), 15025. https://doi.org/10.1038/nrdp.2015.25
Cytokine balance in asthma
Cytokine balance: Numerous factors, including alterations in the number or type of infections early in life, the widespread use of antibiotics, adoption of the Western lifestyle, and repeated exposure to allergens, may affect the balance between Th1-type and Th2-type cytokine responses and increase the likelihood that the immune response will be dominated by Th2 cells and thus will ultimately lead to the expression of allergic diseases such as asthma. | Busse WW, Lemanske RF. Advances in Immunology N Engl J Med 2001; 344: 350-62. Copyright © 2001 Massachusetts Medical Society.

Acute exacerbation triggers:

Contribution of risk factors to the development and/or exacerbation of asthma
Contribution of risk factors to the development and/or exacerbation of asthma. | Holgate, S. T., Wenzel, S., Postma, D. S., Weiss, S. T., Renz, H., & Sly, P. D. (2015). Asthma. Nature Reviews Disease Primers, 1(1), 15025. https://doi.org/10.1038/nrdp.2015.25

Pathophysiology

Airway pathology:

Intermittent and reversible airway obstruction, chronic bronchial inflammation with eosinophils, bronchial smooth muscle hypertrophy and hyperreactivity, and increased mucus secretion.
  1. Bronchoconstriction (dominant physiological event):
  2. Airway edema
  3. Airway hyperresponsiveness
  4. Airway remodeling
Asthma pathogenesis
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Histopathology:

  • Mucous plugs contain,
    • Curschmann spirals (whorls of shred epithelium)
    • Charcot-Leyden crystals (crystalloids made of eosinophil proteins)

Presentation

Asthma clinical findings
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Acute exacerbation of asthma:


Diagnosis

Asthma findings on investigations
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Bronchial (methacholine/histamine) challenge test:

Bronchoprovocation test where patient breathes in nebulized methacholine (M3)/histamine (H1) to provoke bronchoconstriction.
Methacholine Challenge Test
Methacholine Challenge Test. (n.d.). Cambridge University Hospitals. Retrieved July 26, 2022, from https://www.cuh.nhs.uk/patient-information/methacholine-challenge-test/

Spirometry:

  • FEV1 < 80%
  • FVC
  • FEV1/FVC < 0.7
  • FEV25-75
Sample spirometry volume-time and flow-volume curves
Sample spirometry volume-time and flow-volume curves | National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda (MD): National Heart, Lung, and Blood Institute (US); 2007 Aug. Section 3, Component 1: Measures of Asthma Assessment and Monitoring. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7230/

Allergy test:

  • Skin test
  • RAST (Radio-allergo-sorbent allergen-specific IgE)

Management

O-SHIT!

  • Oxygen
  • Salbutamol
  • Hydrocortisone
  • Ipratropium
  • Theophylline

Bronchodilators:

  • Beta-2 sympathomimetics: Salbutamol, Terbutaline, Salmeterol, Formoterol
  • Methylxanthines: Theophylline, Aminophylline
  • Anticholinergics: Ipratropium bromide, Tiotropium bromide

Anti-inflammatory:

  • Corticosteroids (Inhalational): Beclomethasone, Budesonide, Fluticasone
  • Corticosteroids (Systemic): Prednisolone, Hydrocortisone
  • Mast cell stabilizers: Sodium cromoglycate, Ketotifen
  • Leukotriene antagonists: Montelukast, Zafirlukast
    • Block LT1-receptors → ↓ eosinophilic inflammation → Bronchodilation

Novel drugs:

  • Monoclonal antibody against IgEOmalizumab
  • Monoclonal anti–IL-5 antibodies: Mepolizumab, Benralizumab
  • Recombinant soluble interleukin (IL)-4 receptor antagonists: Dupilumab

Acute exacerbation of asthma:


Summary

Asthma
Holgate, S. T., Wenzel, S., Postma, D. S., Weiss, S. T., Renz, H., & Sly, P. D. (2015). Asthma. Nature Reviews Disease Primers, 1(1), 15025. https://doi.org/10.1038/nrdp.2015.25

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